Developmental learning disabilities are a highly prevalent form of cognitive impairment, which present a major public health burden and are associated with poor social outcome and substantial psychiatric morbidity. However, to date no effective pharmacologic treatments have been developed for these severely disabling conditions. Neurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of cognitive disability, as it is a common genetic disorder (incidence 1:3000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein. Specific learning disabilities are the most common neurological complication in children with this disease. The development of a mouse model of the disorder led to the key discovery that increased Ras activity is responsible for the learning deficits in NF1 (Costa et al. Nature Genet 2001). We have recently demonstrated that treatment with the HMG-CoA reductase inhibitor lovastatin, which acts as a potent inhibitor of Ras activity and is commonly used for the treatment of hypercholesterolemia, can reverse the biochemical, electrophysiological and cognitive deficits observed in a mouse model of NF1 (Li et al. Curr Biol. 2005). For the first time, this allows us to assess a pharmacologic treatment for cognitive deficits of patients with a genetic disorder, using a medication that has been validated in pre- clinical studies and for which substantial clinical safety data is available. We now seek to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans. In the proposed randomized, double-blind, placebo-controlled trial, we will study the effect of a 14-week lovastatin treatment on cognitive function of children and adolescents with NF1 using neurocognitive, behavioral, and neurophysiological outcome measures. Findings from this exploratory treatment study will allow us to establish the feasibility of a larger-scale study pursuing these aims. PUBLIC HEALTH RELEVANCE: Neurofibromatosis type 1 (NF1) is a valuable single-gene model for understanding mechanisms of cognitive disability. Our pre-clinical studies have shown that treatment with lovastatin, commonly used for treatment of hypercholesterolemia, can reverse cognitive deficits observed in a mouse model of NF1. In this exploratory treatment grant, we propose to extend these findings to studies in human subjects with NF1, to determine whether analogous changes in brain structure and function are observed following lovastatin treatment in humans.